The co-authors of Invasion of the Prostate Snatchers, blog alternate posts weekly. We invite you to post your comments.

Tuesday, February 25, 2014

Xtandi (enzalutamide), the Star of the 10th Annual Genitourinary Meeting


The GU-ASCO meeting kicks off the first of five annual prostate cancer meetings that are on my calendar to attend every year. The other four meetings are hosted by the American Urological Association (AUA) in May, the PCRI meeting in September, the American Society of Therapeutic Radiation Oncology (ASTRO) that is also in September and the Prostate Cancer Foundation retreat (PCF) that occurs in November.  
Since GU-ASCO is the first meeting of the year, the new scientific research presented sets the tone for the whole Year.  This year’s meeting was dominated by the release of a report showing that Xtandi, a potent oral anti-cancer agent, prolongs life compared to placebo when administered prior to the chemotherapy drug Taxotere (a previously published study has already shown that Xtandi prolongs survival when used after Taxotere).
It’s exciting to see an effective pharmaceutical agent get expanded access. This will lead to a greater number of men benefiting with prolonged survival and better quality of life. The bare bones of this groundbreaking report are summarized here:
Abstract #1: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer. Results of the phase III PREVAIL study.
In this randomized, double-blind, placebo-controlled, multinational phase 3 study, chemotherapy-naive patients with metastatic hormone-resistant disease were treated with either enzalutamide or placebo.
Results: A total of 1,717 men were enrolled. Final results showed a significant benefit of enzalutamide over placebo with a 30% reduction in risk of death and an 81% reduction in risk of radiographic progression or death. At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died.
The findings of this study almost certainly indicate that the FDA will approve Xtandi for use prior to Taxotere and in the near future,  Xtandi will compete head to head with Zytiga and Provenge, both of which are already FDA-approved for men in the pre-chemo category.
The fact that FDA approval is almost guaranteed means that doctors are going to start asking a very important question:  What is the optimal way to sequence these three medications?
Presently there is no clear answer about whether Zytiga should be before Xtandi or vice versa. However, there are several very strong arguments that Dendreon’s product, Provenge, a medication that works by stimulating the immune system, should go first:

1.   Provenge only takes 6 weeks to administer, so there is no problem adding other anticancer agents after Provenge administration is complete.

2.   Immune treatments in general are thought to work better when initiated at an earlier stage, before the cancer becomes more entrenched and starts to suppress immune function.

3.   Provenge changes the immune system in a fashion that keeps working indefinitely after the initial 6-week treatment period is passed.

4.   Because insurance only pays for Provenge in men with rising PSA levels, starting Xtandi or Zytiga, both effective in lowering PSA, can substantially delay the initiation of Provenge.   
There seems to be broad consensus that Provenge should be first in line.  The real question then is, “What should come second, Xtandi or Zytiga?”

At the GU-ASCO meeting there were a number of reports, including a report from our office, that show reduced anticancer effects of Xtandi when used after Zytiga.  This is hardly surprising since the phenomena of progressively increasing cancer resistance with each cycle of therapy have been known about for 30 years. Preliminary reports also show a reduced Zytiga response-rate when it is used after Xtandi.

While these reports document that the first agent selected is likely to be used for a much longer time period than the agent that follows, so far there are no studies evaluating whether sequencing  affects overall survival.  Xtandi clearly has reduced anticancer activity after Zytiga. The same, however, has also been observed in reports evaluating Zytiga in men who have previously failed Xtandi.

The jury is still out. Until further comparative studies are performed, no one knows if there is an advantage to using Zytiga first or Xtandi first.  Presently however, I think most experts are assuming that Xtandi and Zytiga seem to have similar overall anti-cancer potency, the preference of sequencing one agent over the other to be first in line is unlikely to have a major impact on overall longevity.

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